Catalytic Batch and Continuous Flow Production of Highly Enantioenriched Cyclohexane Derivatives with Polymer-Supported Diarylprolinol Silyl Ethers

Abstract

Diarylprolinol silyl ethers immobilized onto polystyrene have been employed as catalysts in the enantioselective domino Michael-Knoevenagel reaction of dimethyl 3-oxoglutarate and 3-substituted acrolein derivatives, including aliphatic ones. The best catalyst allows the preparation of highly functionalized cyclohexane derivatives in a straightforward and efficient manner, both under batch and continuous flow conditions.

Key words

asymmetric organocatalysis - domino process - Michael addition - Knoevenagel condensation - flow reactors

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15

See Supporting Information for details.

16

General Procedure for the Domino Michael-Knoevenagel Process of α,β-Unsaturated Aldehydes and Dimethyl 3-Oxopentanedioate: Benzoic acid (0.05 mmol), the corresponding aldehyde (0.25 mmol) and dimethyl 3-oxopentanedioate (0.275 mmol) were added to catalyst 5 (0.025 mmol) previously swollen in CH₂Cl₂ (1 mL). The suspension was shaken at r.t. for the time indicated in Table  [²] and then directly filtered. The resin was rinsed with CH₂Cl₂ (3 × 1 mL) and the organic filtrate was concentrated under reduced pressure. MeOH (1 mL) and NaBH₄ (0.25 mmol) were added to a solution of the resulting crude in CH₂Cl₂ (0.5 mL) at 0 ˚C, which was stirred at that temper-ature for 20 min. After addition of the pH 7 phosphate buffer, the organic materials were extracted with CH₂Cl₂ and the combined organic phase was dried over Na₂SO₄, and then concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (CH₂Cl₂-EtO₂) to afford 7.

17

The deposition number at the Cambridge Crystallographyc Data Centre is CCDC 804763.

18

These recycling experiments show the results obtained in six consecutive runs. After each run, the reaction mixture was filtered and the solid-supported catalyst was washed with CH₂Cl₂ and directly reused.